The virus causing the acquired immunodeficiency syndrome (AIDS) is known by different names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up until now, two distinct families have been identified, i.e. HIV-1 and HIV-2. Hereinafter, HIV will be used to generically denote these viruses.
One of the critical pathways in a retroviral life cycle is the processing of polyprotein precursors by retroviral protease. For instance, during the replication cycle of the HIV virus, gag and gag-pol gene transcription products are translated as proteins, which are subsequently processed by a virally encoded protease to yield viral enzymes and structural proteins of the virus core. Most commonly, the gag precursor proteins are processed into the core proteins and the pol precursor proteins are processed into the viral enzymes, e.g., reverse transcriptase and retroviral protease. Correct processing of the precursor proteins by the retroviral protease is necessary for the assembly of infectious virions, thus making the retroviral protease an attractive target for antiviral therapy. In particular for HIV treatment, the HIV protease is an attractive target.
Several protease inhibitors are on the market or are being developed. Hydroxyethyl-amino sulfonamide HIV protease inhibitors, for example 4-aminobenzene hydroxyethylamino sulfonamides, have been described to have favourable pharmacological and pharmacokinetic properties against wild-type and mutant HIV virus. Amprenavir is a commercially available exponent of this 4-aminobenzene hydroxyethylamino sulfonamide class of protease inhibitors. A process for the synthesis of amprenavir is described in WO99/48885 (Glaxo Group Ltd.).
4-Aminobenzene hydroxyethylamino sulfonamides may also be prepared according to the procedures described in EP 715618, WO 99/67254, WO 99/67417, U.S. Pat. No. 6,248,775 and WO 2007/060253, and in Bioorganic and Chemistry Letters, Vol. 8, pp. 687-690, 1998, Bioorganic and Medicinal Chemistry Letters 14 (2004)959-963 and J. Med. Chem. 2005, 48, 1813-1822, all of which are incorporated herein by reference.
One protease inhibitor which has been approved in the USA for human clinical use for the treatment of retroviral infections is the compound having the USAN approved name darunavir with the chemical name (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropyl-carbamate and the structure of formula (A):

Darunavir is employed in the clinic in the form of its ethanolate solvate derivative.
Methods suitable for the preparation of darunavir are disclosed in WO 99/67417 (USA, The Secretary, Dpt. of Health and Human Services) and WO 99/67254 (USA, The Secretary, Dpt. of Health and Human Services and The Board of Trustees of the University of Illinois), and in WO 03/106461 (Tibotec N.V.) and WO 2005/063770 (Tibotec Pharmaceuticals).
EP 1466896 (Ajinomoto KK) relates to a process for producing crystalline benzenesulfonamide derivatives. In particular, it provides a crystallization for (2R,3 S)—N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzene-sulfonamide, which is an intermediate of interest for the preparation of darunavir.
In order for a chemical route to be suitable for industrial scale, it should produce compounds in acceptable yields and purity while being easy and simple to carry out, as well as cost-effective. As such, there has been found a new process for the synthesis of darunavir which is amenable for use on an industrial scale.
In particular, the present invention provides a convenient process for the production of darunavir and intermediates, solvates, addition salts, polymorphic and/or pseudopolymorphic forms thereof on an industrial scale.
The reagents further used in said process are safe and available in bulk. Furthermore, each step of said method is performed at controllable conditions and provides the desired compound in optimal yields. Moreover, each step of said process is performed stereoselectively, which allows the synthesis of pure stereoisomeric forms of the desired compounds. The last stage of the process, which involves the reduction of a nitro group to form an amino group, is especially advantageous as it provides the desired compound in a relatively pure form with minimal amounts of associated impurities. Also, many of the stages can be performed sequentially without removal of the intermediate compounds from the reaction vessel.
Other objects and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying examples.